Placebo Effect Reaches Down Spine to Calm Pain Neurons

Doctors have long known that mere words or inert pills can soothe pain by creating the expectation of relief. Now researchers in Germany have reported that this placebo effect is not just in your head but reaches down to the pain-transmitting neurons of the spine.

The scientists describe their research in two papers, one in the Oct. 16 issue of Science, the other in the Aug. 27 issue of Neuron. Together these studies suggest that a typical placebo pain-reducing effect works through the descending pain control system, a known mechanism of pain relief involving both the brain and spinal cord. Triggered by the release of morphine-like opioid neurotransmitters in the brainstem, normally by pain or stress, this system can directly inhibit the activity of pain neurons in the spine.

From previous studies, scientists suspected that a placebo can also switch on this system by causing the release of opioids, also called endorphins. The new research firms up that theory, says Fabrizio Benedetti, a neuroscientist at the University of Turin who has done extensive work in this field. “I believe it is the conclusive demonstration that the opioidergic systems mediate placebo analgesia, at least in some circumstances,” he says.

The research was led by Falk Eippert, a neuroscientist at the University Medical Center Hamburg-Eppendorf, a large research hospital in Hamburg. In the study reported in Science, Eippert and his colleagues applied creams to two square patches of the forearms of 13 people, telling them that one cream contained the strong painkiller lidocaine, while the other contained only an inert “control” cream. In fact, both creams were inert. The researchers then applied painful heat to the two areas. Compared with the “inert” cream area, the subjects gave the “lidocaine” patch—the placebo—25 percent lower pain ratings on average. Functional magnetic resonance imaging (fMRI) data also showed a difference in the activity of the spinal neurons that supply pain signals to the skin areas.

In the earlier study, reported in Neuron, Eippert and his colleagues used fMRI to show that a placebo painkilling effect appeared to activate the upper structures of the descending pain control system, including the hypothalamus and parts of the brainstem as well as a prefrontal brain region, the rostral anterior cingulate cortex. All of this activity was significantly reduced when the researchers gave subjects the opioid-blocking drug naloxone, strongly indicating the involvement of opioids.

Previous studies have implicated opioids in the placebo effect, using tests involving naloxone as well as positron emission tomography imaging of opioid-related brain activity. So the involvement of these molecules now seems established.

Multiple placebo effects?

But as Eippert points out, the placebo pain-relief effect isn’t necessarily limited to opioids and the descending pain-control system. “The spinal inhibition we see is only one of several mechanisms for the response of placebo analgesia. It’s not the mechanism,” he says.

The placebo effect appears to be a manifestation of a very broad and basic motivational feature of the brain, by which the mere expectation of an event can make the brain react—to a large extent—as if the event has already happened. That reaction may involve whatever brain systems are normally engaged by an event, not just opioid systems. A classic example of conditioned expectation is when a dog salivates at the sound of his usual dinner bell.

When a patient is given an inert pill and told that it will bring pain relief, the resulting placebo effect may come mainly from the release of opioids in the brain. But at least in some cases, alternate pain-relieving mechanisms appear to be triggered. In a placebo-effect study in 1999, Benedetti’s group first conditioned subjects with a non-opioid pain reliever drug, and found that the covert replacement of the drug with a placebo brought about pain relief that was not blocked by naloxone—indicating that the effect was not caused by opioid release.

“Little is known about non-opioid mechanisms, says Benedetti, “but several labs are starting to investigate [the involvement of] other neurotransmitters.”